Method for preparing terlipressin

Abstract

The invention relates to a method for preparing terlipressin, and belongs to the technical field of polypeptide synthesis. The method comprises the steps that terlipressin peptide resin is synthesized through a fragment condensation method, 3-12 fragments are synthesized through a solid phase method, 1-2 fragments are connected to 3-12 solid phase amino-acid resin, full-peptide resin is obtained, and the terlipressin is obtained after cracking and cyclizing. Due to the fact that Boc-Gly-Cly-OH is adopted as a raw material, lack of glycine impurities is reduced, the operation step of removing glycine protection groups at an N terminal is omitted, product purity is improved, and the total cost is obviously reduced.

Description

technical field [0001] The invention relates to the technical field of polypeptide synthesis, in particular to a preparation method of terlipressin. Background technique [0002] Terlipressin, the English name is Terlipressin, the molecular formula is: C 52 h 74 N 16 o 15 S 2 , the molecular weight is 1227.4 and the structural formula is, the structural formula: [0003] [0004] Terlipressin is clinically used for the treatment of severe acute esophageal variceal rupture and bleeding, severe acute gastric and duodenal ulcer bleeding, acute erosive gastritis or hemorrhagic gastritis, adjuvant treatment of pancreas, gallbladder and intestines, and diabetic ketosis The adjuvant treatment of acidosis, terlipressin itself is inactive, and it is slowly converted into active lysine vasopressin after the three glycine residues at the N-terminal are removed by the action of aminopeptidase in vivo. It is used for the treatment of acute esophageal variceal bleeding caused by ...

AI Technical Summary

Problems solved by technology

[0006] Mentioned in the Czechoslovakian patent CZP281589 is a liquid phase synthesis method, with Boc-Gly-chloromethyl resin as the starting material, followed by Boc-Lys (Tos), Boc-Pro, Boc-Cys(Bzl), Boc-Asn, Boc-Gln, Boc-Phe, Boc-Tyr(Z), Boc-Cys(Bzl), Boc-Gly, Boc-Gly, Boc-Gly, and then through ammonia solution, Terlipressin is produced through a series of reactions such as sodium hydrolysis and oxidation. This method has a low efficiency of incorporation of peptides, only 75%. The process takes a long time, and the three wastes in the process are serious, which is not conducive to large-scale production.

[0007] What is mentioned in Chinese patent CN1865282B is a solid-phase synthesis method, using RinkAmide resin as a starting material, sequentially linking Fmoc-protected amino acids to a solid-phase carrier according to the peptide sequence of terlipressin, and then adding a peptide-cutting reagent to cut Peptides were precipitated by adding ether to obtain the reduced crude product, which was oxidized by air at a pH of 7.5-10.0 to obtain the oxidized crude product, and finally separated and purified by C18 (or C8) column to obtain terlipressin. During the preparation process, it is easy to produce des-Gly 1 Terlipressin impurities (terlipressin lacking a glycine), seriously affect the yield of the entire process; the oxidation process takes a long time, prone to peptide chain breakage

[0008] What is mentioned in Chinese patent CN102408471A is the fragment condensation method, the 1-3 fragments are synthesized in the liquid phase, and then this fragment is connected to the fragment 4-12-resin synthesized in the solid phase to obtain the terlipressin peptide resin, which is cut , Oxidation to obtain the crude peptide of terlipressin, and finally use C18 column separation and purification to obtain the target product, this method is easy to produce des-Gly during the preparation process 1 ,Gly 2 ,Gly 3 Terlipressin impurities (missing N-terminal three glycines), and the synthesis of 1-3 fragments is difficult and costly, and it is easy to form impurities missing glycine and polyglycine

Images